A phase Ib/II, multicenter, open-label study of AK104, a PD-1/CTLA-4 bispecific antibody, combined with chemotherapy (chemo) as first-line therapy for advanced gastric (G) or gastroesophageal junction (GEJ) cancer: 2-Year update data.
Authors: Jiafu Ji, Lin Shen, Ziyu Li, Xiangyu Gao, Ke Ji, Ye Chen, Nong Xu, Tianshu Liu, Nong Yang, Haijun Zhong, Changzheng Li, Zengqing Guo, Qingxia Fan, Xiaoyan Lin, Zhifang Yao, Wei Liu, Zhongmin Maxwell Wang, Baiyong Li, Yu Xia
Journal: Journal of Clinical Oncology (2023)

4031 Background: Anti-PD-1 monoclonal antibodies plus chemo as first-line therapy for advanced G/GEJ cancer yields OS and PFS benefits compared to chemo alone while the survival benefits are limited, especially in patients with low PD-L1 expression (CPS&lt;5). Simultaneous blockade of the PD-1 and CTLA-4 pathways has shown synergistic anti-tumor activity and has been proven effective across multiple cancer types. This phase Ib/Ⅱ dose-escalation study evaluated the safety and efficacy of AK104, a PD-1/CTLA-4 bispecific antibody, combined with XELOX or modified XELOX (mXELOX) in the first-line treatment of G/GEJ cancer cohorts (NCT03852251). Methods: Pts with unresectable advanced G/GEJ adenocarcinoma and no prior systemic therapy, regardless of PD-L1 status, were enrolled, excluding known HER2-positive pts. Enrolled patients received AK104 (4 mg/kg, 6 mg/kg or 10 mg/kg Q2W, 10 mg/kg or 15mg/kg Q3W) + chemo (mXELOX Q2W or XELOX Q3W). The primary endpoint was safety and the objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Results: As of 31 Oct. 2022, 98 pts were enrolled with only 4 pts in 10 mg/kg Q3W, the safety and efficacy of the regimen of 10mg/kg Q3W will be reported in the phase III study and not be reported here. 94 pts were enrolled with median age of 62.7 years (range: 29–75), 70.2% male, 62.8% ECOG PS 1, and 45.7% liver metastasis. The median follow-up was 24.0 months (range: 0.5-33.3). 88 patients (94%) had at least one post-baseline tumor evaluation. The ORR was 68.2% (60/88), with 5 (5.7%) complete responses and 55 (62.5%) partial responses. The disease control rate (DCR) was 92.0% (81/88). The median duration of response (DoR) was 9.69 months (95%CI, 5.82 to 14.00). The median PFS was 9.20 months (95%CI, 6.67 to 10.48). The median OS was 17.41 months (95%CI, 12.35 to 29.77). In pts with PD-L1 CPS≥5 and CPS＜5, the median OS was 20.24 months and 17.28 months, respectively. Treatment-related adverse events (TRAEs) occurred in 97.9% of pts. The most frequent were platelet count decreased (62.8%), white blood cell count decreased (61.7%), neutrophil count decreased (59.6%), anemia (51.1%), aspartate aminotransferase increased (33.0%), nausea (30.9%), and vomiting (30.9%). Grade ≥3 TRAEs occurred in 69.4% of pts. No new safety signals were identified. Conclusions: AK104, combined with mXELOX/XELOX, showed promising activity and manageable safety in previously untreated patients with advanced G/GEJ adenocarcinoma. AK104 + chemo represents a potential new first-line treatment option for these pts. A phase III study of AK104 combined with chemo as first-line therapy for G/GEJ cancer is underway (NCT05008783). Clinical trial information: NCT03852251 .